A Bird's Eye View of Atropisomers Featuring a Five-Membered Ring Damien Bonne*[A] and Jean Rodriguez*[A]

A Bird’s Eye View of Atropisomers Featuring a Five-Membered Ring Damien Bonne, Jean Rodriguez

To cite this version:

Damien Bonne, Jean Rodriguez. A Bird’s Eye View of Atropisomers Featuring a Five-Membered Ring. European Journal of Organic Chemistry, Wiley-VCH Verlag, 2018, 2018 (20-21), pp.2417 - 2431. 10.1002/ejoc.201800078. hal-01907622

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Atropisomerism A Bird's Eye View of Atropisomers Featuring a Five-Membered Ring Damien Bonne*[a] and Jean Rodriguez*[a]

Abstract: An atropisomer is a member of a subclass of re- chemical bond. After a short introduction, the occurrence of stricted rotational conformers – this restricted rotation giving atropisomers in nature is presented, as well as the synthetic rise to stereogenic sigma bonds – that can be isolated as sepa- efforts – encompassing non-stereoselective and diastereo- rate chemical species. Most atropisomer are six-membered-ring selective strategies, together with an update on very recent biaryl or heterobiaryl derivatives. The aim of this microreview is enantioselective approaches – devoted to such axially chiral to shed light on a less common class of atropisomers, those compounds. Finally, a special focus is placed on their important containing at least one five-membered hetero- or carbocycle utilization as original and efficient ligands for metal complexes. and displaying variously a stereogenic C–N, C–C, or even N–N

1. Introduction N–N bond have received less attention.[6i] This situation is basi- cally due to the increased distance between the ortho-substitu- Nonracemic axially chiral systems of type 1[1] (Scheme 1) are ents (R1 to R4) next to the axis, which is responsible for lower recognized as central elements in many scientific domains, with barriers to rotation, hampering the conformational stability notably numerous applications in catalyst design,[2] drug dis- (Scheme 1). covery,[3] and materials sciences,[4] and are also widely represented in nature. Among them, six-membered carbocyclic – and, to lesser extent, heterocyclic – atropisomers[5] have com- manded huge attention over the years and still constitute a central topic of research worldwide, resulting in the development of many elegant synthetic approaches.[6] In sharp contrast, atropisomeric species featuring one or even two five- membered rings connected variously through a C–C, C–N, or

[a] Aix Marseille Université, CNRS, Scheme 1. Situation of six- versus five-membered atropisomeric systems. Centrale Marseille, iSm2, France E-mail: [email protected] or [email protected] Pioneering observations and experimental determinations of http://ism2.univ-amu.fr/fr/stereo/stereo ORCID(s) from the author(s) for this article is/are available on the WWW barriers to rotation highlight the crucial effect of ortho-substitu- under https://doi.org/10.1002/ejoc.201800078. ents. It has been proposed by Oki that a pair of atropisomers

Damien Bonne was born in Epinal (France) in 1979. After studying chemistry at the Ecole Supérieure de Chimie de Lyon (CPE Lyon, France), he completed his Ph.D. in 2006 under the supervision of Prof. J. Zhu, working on isocyanide-based multicomponent reactions. He then moved to the University of Bristol (UK) to join the group of Prof. V. A. Aggarwal as a postdoctoral associate. Since 2007 he has been working as a “Maître de Conférences” (associate professor) at Aix-Marseille University (France). He passed his habilitation (HDR) in 2015 and his research interests include the development of new organocatalyzed methodologies and their application in stereoselective synthesis.

Jean Rodriguez was born in Cieza (Spain) in 1958, and in 1959 his family emigrated to France. After studying chemistry at the University of Aix-Marseille (France), he completed his Ph.D. as a CNRS researcher with Prof. B. Waegell and Prof. P. Brun in 1987. He completed his Habilitation in 1992, also at Marseille, where he is currently Professor and Director of the UMR-CNRS-7313-iSm2. His research interests include the development of multiple bond-forming transformations including domino and multicomponent reactions, and their application in stereoselective organocatalyzed synthesis. In 1998 he was awarded the ACROS prize in Organic Chemistry, in 2009 he was awarded the prize of the Division of Organic Chemistry from the French Chemical Society, and in 2013 he became a “Distinguished Member” of the French Chemical Society.

Eur. J. Org. Chem. 2018, 2417–2431 2417 © 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim Microreview should exhibit a minimum energy barrier of 93 kJ mol–1, to en- The first of these families is that of the optically pure poly- sure a half-life of at least 1000 seconds at room temperature[7] brominated biindoles 2 from marine blue-green alga Rivularia and to offer reasonable expectation of the convenient separa- firma, isolated in 1982 and including the four C–C-bonded con- tion of the two enantiomeric atropisomers.[8] geners 2a–d and the two C–N-bonded congeners 2e and 2f In this context, the aim of this microreview, after a brief his- (Scheme 2a).[9] torical background highlighting their natural occurrence, is to Another C–N-bonded carbazole alkaloid family, named give an overview on the preparation of atropisomers from ne- murrastifolines A (3a), B (3b), and F (3c), was isolated eleven glected pioneering achievements up to more contemporane- years later from the acetone extract of the root of the plant ous selective approaches, including an update on very recent Murraya koenigii (Scheme 2b).[10] From the substitution pattern enantioselective syntheses. The last section is devoted to their of the axially chiral C–N-bonded phenyl ring of murrastifolines A utilization as efficient ligands for metal complexes, followed by and B, lacking any ortho-substituent, rapid rotation at the biaryl their efficient utilization as ligands for metal complexes. axis was suspected, whereas murrastifoline F, bearing four ortho-substituents next to the axis, was expected to be configu- rationally stable. This was established by Bringmann and collab- 2. In Nature orators in 2001, both through a very high calculated (AM1) atropisomerization barrier of 165 kJ mol–1 and by the unique Both axially chiral C–C- and C–N-bonded atropisomers contain- total synthesis of the F analogue, showing its presence in the ing five-membered rings exist in nature, essentially in three root extract as a 56:44 mixture in favor of the M enantiomer.[11] small, rare families featuring one or two five-membered rings from the indole, carbazole, or pyrrole series. However, their iso- More recently, the two new axially chiral metabolites lation and characterization were achieved only at the end of (–)-marinopyrrole A (4a) and (–)-marinopyrrole B (4b) were iso- the last century (Scheme 2). lated after cultivation of an obligate marine Streptomyces strain[12] and showed potent antibiotic activities against methicillin-resistant staphylococcus aureus (Scheme 2c).[13] Two years after their isolation, two different total syntheses of (±)-marinopyrrole A were reported contemporaneously by the groups of Li[12c] and Sarli,[12d] with nine steps and 30 % yield and six steps and 22 % yield, respectively.

2. Non-Stereoselective Syntheses The first synthesis of an axially chiral five-membered-ring compound was that of C–N-bonded[14] arylpyrrole 5a, reported back in 1931 by the group of Adams,[15] followed by a series of pa- pers dealing with the preparation of the related arylcarb- azole[16] 5b and the dipyrryl biphenyl 6[17] (Scheme 3). In all these studies, the racemic atropisomers obtained from the required 1,5-diketones and anilines in a Paal–Knorr heterocycliza- tion in the case of 5a and 6 or through the Ullman-type coupling of o-iodobenzoic acid with 3-nitrocarbazole in that of 5b were resolved by means of the corresponding brucine salts. In- terestingly, for pyrrole 5a and carbazole 5b the two enantiomers were found to be relatively stable in boiling ethanol but to undergo total thermal racemization in the presence of NaOH.

Scheme 2. Naturally occurring C–C- and C–N-bonded axially chiral arylazoles. Scheme 3. First families of axially chiral N-arylpyrroles 5 and 6.

After these pioneering contributions, the experimental deter- also demonstrated the possibility of forming a rather stable mination of steric barriers in atropisomers containing five-mem- 12-membered-ring diether atropisomer with a slightly higher bered rings became a central research domain of early confor- barrier to rotation. mational analysis. This was facilitated by the concomitant devel- This unusual intramolecular hydrogen bond effect was ex- opment of chiral liquid chromatography, allowing efficient sep- ploited four years later by Shimizu's group for the design of arations of atropisomers as thoroughly studied by Roussel and original simple molecular rotors featuring compound 7,aN-8- collaborators, starting in 1985.[18a–18d] This strategy was applied quinolinylsuccinimide framework (Scheme 6).[19d,19e] The au- to N-arylthiazolinethione derivatives and their oxygen ana- thors clearly established that protonation of the quinoline re- logues, and later on by Pirkle's, Mannschreck's, and Doğan's sulted in a dramatic lowering of the barrier to rotation, due to groups, notably with related N-aryloxazolinones[18e–18g] and N- the stabilization of a planar transition state through the forma- arylthioxo-oxazolidinones or N-arylrhodanines.[18h,18i] These tion of an intramolecular hydrogen bond between the proto- comparative studies of large series of compounds clearly nated nitrogen atom and the imide carbonyl group. Interest- showed the crucial effect of ortho-substitution on the value of ingly, the acceleration of the rotation is reversible and can be the barriers to rotation, which fluctuated from 38.9 kJ mol–1 stopped by addition of base. The determining presence of the for ortho-unsubstituted derivatives up to ≥134 kJ mol–1 nitrogen atom in this specific 8-position was unambiguously (Scheme 4). Interestingly, some specifically functionalized N- established, with no effect being observed with the corre- arylthiazolinethione nuclei have been used either as enantio- sponding control rotors from both the 6-substituted quinoline selective anion receptors for amino acid derivatives[18j] or as and the naphthalene series. The same group, upon guest com- new atropisomeric chiral probes to study supramolecular orga- plexation of an acetate ion, observed a closely related effect on nization in porphyrin self-assemblies.[18k] the barrier to rotation with N-arylsuccinimides containing a urea recognition group.[19e]

Scheme 6. Acid-accelerated N-8-quinolinylsuccinimide molecular rotor.

Scheme 4. Variations of the barriers to rotation in N-arylthiazoline derivatives. Mintas and collaborators also reported detailed pioneering More recently, the groups of Doğan and Roussel independ- studies dealing with the synthesis and chromatographic separa- ently reported complete experimental and theoretical studies tion of compounds 8, a series of N-aryl- and N-heteroaryl-2,5- relating to the synthesis of, and the evaluation of the barriers dimethylpyrrole-3-carbaldehydes variously containing simple to rotation in, a series of original atropisomeric iminothiazol- phenyl, quinolinyl, thiazolyl, pyridyl, and 6-purinyl groups, and idinones and iminothiazolines, respectively (Scheme 5).[19a–19c] the determination of their barriers to racemization, either ex- [20] In all of these studies the resolution of atropisomeric enantio- perimentally or by calculation (Scheme 7a). Here also, the mers was achieved by chromatography on chiral supports. In crucial effect of steric factors next to the axis in reaching the –1 the case of N-aryliminothiazolines, it was found that the barriers required minimum of 100 kJ mol for the barrier to rotation significantly decrease when X = OH through the creation of an was clearly highlighted. Accordingly, in this series only N- internal hydrogen bond with the nitrogen atom of the imino phenyl- and N-quinolinylpyrroles gave room-temperature- group, as was corroborated by DFT calculations. The authors stable atropisomers with high calculated free enthalpies of activation: ∆G‡ = 128 and 130 kJ mol–1, respectively. Related enantiopure axially chiral N-phenylpyrrolidones 9 and N-phenyltria- zolones 10 were also obtained by resolution of the corresponding menthol and naproxen esters, respectively (Scheme 7b).[21] More recently, Sugane and co-workers proposed an efficient means of resolution using (1R,2S)-(–)-2-amino-1,2-diphenyl- ethanol for the synthesis of the stable atropisomeric N-phenyl- 1,2,4-triazole (aR)-(–)-11, which displayed a barrier to rotation of 127 kJ mol–1 and exhibited interesting GlyT1-inhibiting properties (Scheme 8).[21c] In 2016, Ciogli, Mazzanti, and Perumal exploited a new domino reaction between aryl isocyanates 12 and commercially Scheme 5. Variations of the barriers to rotation in N-aryliminothiazolidinone available 1,4-dithiane-2,5-diol for the synthesis of axially chiral and -iminothiazoline derivatives. N-arylthiazolinethione derivatives 14 (Scheme 9).[22] A complete

Scheme 10. C3–C3′-bonded chiral atropisomeric bithienyl derivatives (+)- and (–)-15.

Other recent examples of related C–C-bonded atropisomeric derivatives of the bis-pyrrole type have been proposed inde- pendently by Bringmann's and Chmielewski's groups for the design of axially chiral BODIPY dyes 16 and 17 or of bis(N- confused porphyrin) 18 as a semirigid receptor with memory of chirality, respectively (Scheme 11).[24] Scheme 7. N-Aryl and N-heteroaryl axially chiral atropisomers 8–10.

Scheme 8. Biologically active N-phenyltriazole 11.

combined dynamic NMR and HPLC study both of the transient hemiaminal intermediates 13 and of the N-arylthiazolinethiones 14 allowed the determination of a low barrier to rotation of 90.5 kJ mol–1 for R = H, in agreement with fast atropisomerization at room temperature. In sharp contrast, for R = Me the Scheme 11. C–C-bonded atropisomeric BODIPY derivatives 16 and 17 and barrier to rotation was estimated to be higher than porphyrin derivative 18. 150.5 kJ mol–1, allowing the separation of the two stable Finally, the imidazole nucleus has also been used to elabo- enantiomers by chiral HPLC. rate C–C-bonded atropisomeric 15- and 16-membered macrocycles 20a and 20b from precursor 19 by ring-closing metathesis followed by hydrogenation. These macrocycles 20a and 20b show high barriers to rotation of 170.9 and 109.5 kJ mol–1, corresponding to half-lives of racemization at 25 °C of several trillion years and 40 days, respectively (Scheme 12).[25]

Scheme 9. One-pot synthesis of N-arylthiazolidinethiones 14.

A new electroactive chiral polyheterocyclic organic film based on axially chiral C–C-bonded bithienyl assembies was de- Scheme 12. C–C-bonded atropisomeric 15- and 16-membered macrocycles signed and synthesized by Sannicolò's group. The racemic ma- 20a and 20b. terial was obtained by Stille coupling, and the two monomeric optically pure atropisomers (aR)-(–)-15 and (aS)-(+)-15 were ob- Since the first report of the axially chiral C–N-bonded aryl- tained by separation on chiral HPLC and present a very high pyrrole 5a in 1931,[15] the resolution of racemic mixtures either barrier to rotation of 167 kJ mol–1 (Scheme 10).[23] chemically or chromatographically has emerged as a central

Eur. J. Org. Chem. 2018, 2417–2431 www.eurjoc.org 2420 © 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim Microreview tool for the production of enantiomerically pure atropisomers the dia- containing five-membered rings. These have found numerous stereoselectivity was observed in the case of compound 26 applications, notably in the design of metal complexes. Com- (Scheme 13b, down arrow). Interestingly, and in agreement plementarily to these robust techniques, original stereoselective with their expectations, chiral compounds 24, 25a, and 26 were synthetic approaches have appeared during the two last stable at room temperature and started to isomerize above decades and are presented in the following sections together 120 °C, whereas 25b never isomerized even at 150 °C. At the with some specific applications of the resulting atropisomers. same time, the Kishikawa group reported a related atropodiastereoselective amination of 23 affording the corresponding N- benzyl- and N-(1-phenylethyl)succinimides 27a and 27b with 3. Stereoselective Syntheses diastereoselectivity ranging from 81:19 to >99:1 dr.[26d] The barriers to rotation were measured by 1H NMR and were found to 3.1. Diastereoselective Functionalizations of Axially Chiral be around 120 kJ mol–1 for both atropisomers (Scheme 13b). Atropisomers After these pioneering contributions with the prochiral N- The first representative, based on atropodiastereoselective de- arylmaleimides 21–23, Taguchi and co-workers proposed a sim- symmetrization of prochiral N-arylmaleimide 21, is that of Cur- ple synthesis of axially chiral maleimide (+)-22 with 96 % ee and ran et al. in 1994.[26b] They reasoned that the presence of a a half-life for racemization of 15 h at 80 °C allowing its utiliza- [27a] large ortho-tBu substituent should provide a high enough bar- tion in further stereoselective transformations (Scheme 14). rier towards rotation around the C–N axis, for efficient stereo- The synthesis started from (R)-2-methylsuccinic acid (28) and selective synthesis. Hence, the addition of a tBu radical to 21 ortho-tBu-aniline (29), followed by an oxidative selenoxide elim- under the Giese conditions gave 24 with high diastereoselecti- ination from the resulting major diastereomer (1.3:1 dr) of suc- vity (Scheme 13a, right). Alternatively, endo-selective Diels–Al- cinimide 30 obtained with 96 % ee after recrystallization. As der cycloaddition either with 2,3-dimethylbuta-1,3-diene at expected from Curran's work, the thermal or Lewis-acid-cata- 80 °C or with cyclopentadiene at 25 °C afforded the cycload- lyzed endo-selective Diels–Alder reaction between (+)-22 and ducts 25a and 25b with the same high diastereoselectivity cyclopentadiene proceeded with good yields and high dia- (Scheme 13a, top). In addition, the authors demonstrated simi- stereoselectivities to furnish 25c with 97:3 dr and 96 % ee lar efficiency in 1,3-dipolar cycloaddition with neopentaneni- (Scheme 13a, top). trile oxide, although an important effect of the temperature on

Scheme 14. Diastereoselective preparation of axially chiral maleimide (+)-22.

In a subsequent contribution, the same group disclosed an original three-step synthesis of 33, a new optically active axially chiral N-arylpyrrolidone, with ≥98 % ee from (S)-5-(methoxy- methyl)butyrolactone (31) and aniline 29 (Scheme 15).[27b] In- terestingly, the lithium enolate of 32 underwent diastereo-

Scheme 13. Atropodiastereoselective desymmetrizations of maleimides 21– 23. Scheme 15. Diastereoselective axially chiral N-arylpyrrolidones 32 and 33.

Eur. J. Org. Chem. 2018, 2417–2431 www.eurjoc.org 2421 © 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim Microreview selective functionalization with various electrophiles, leading to non is due to a quite significantly lower barrier to rotation for unusual 3,5-cis-disubstituted 2-pyrrolidinone derivatives 33. the adducts 39 than for the starting heterodienes 38, by about Here also, the ortho-tBu group ensures a high barrier to rotation 20 kJ mol–1. and shields the Si face of the enolate, resulting in the uncom- mon 3,5-cis selectivity. It is interesting to note that changing the tBu– group to a –OBn or even a –OTBDPS group resulted in free rotation around the C–N axis at room temperature. The usually high stereoselectivity found for cycloadditions has been exploited to access various families of original atropisomeric derivatives from easily accessible unsaturated precursors. For example, simple room-temperature-stable axially chiral N-aryl-substituted monothiosuccinimides 34 were proposed by Sakamoto and collaborators in 2003 as interesting partners in chemo-, regio-, and diastereoselective [2+2] photocycloaddition to 1,1-diphenylethylene, leading to spirothietanes 35 in good yields (Scheme 16).[28] In this transformation, the steric hindrance of the ortho-substituent was crucial and per- fectly controlled the addition to form 35 exclusively.

Scheme 18. exo-Selective hetero-Diels–Alder cycloaddition of N-arylthiazolidinethiones 38.

Complementarily to cycloadditions, simple chemical transformation of N-arylindole 40 was used by Nakazaki and collaborators to prepare the stable chiral nonracemic N-arylisatin 41, ob- tainable in optically pure form by chiral HPLC and featuring a –1 [31] Scheme 16. Photocycloaddition of N-aryl-substituted monothiosuccinimides barrier to rotation of 130 kJ mol (Scheme 19). The racemic 34. 41 constituted an interesting synthetic starting material for obtaining functionalized N-aryloxindole derivatives 42 through In 2011 Savage's group reported an interesting atropisomeric diastereoselective nucleophile additions, alkylations, and cyclo- facial selectivity during regioselective (1,3)-dipolar cycloaddi- additions. tion between benzonitrile oxide and racemic axially chiral N- arylmethylenehydantoins 36 (Scheme 17).[29] The nature of the ortho-substitution (R group) was crucial for the attainment of high diastereoselectivities, ranging from 2.5:1 to >99:1 ratios of anti-37 to syn-37. Interestingly, the best result was obtained with R = NO2, leading to anti-37 only, probably due to addi- tional electrostatic repulsion with the approaching nitrile oxide dipole.

Scheme 19. Axially chiral N-arylindole, -isatin and -oxindole atropisomers 40– 42.

Utilization of enantiopure precursors was reported by Siva- guru's group in the photochemical type II cyclization of non- biaryl atropisomeric benzoylformamides 43 to afford N-aryl- oxazolidinones 44 (Scheme 20a).[32] The cyclization proceeds Scheme 17. (1,3)-Dipolar cycloaddition to N-arylmethylenehydantoins 36. with chiral memory, resulting in the preservation of the config- Also of interest is the reactivity of benzylidene N-arylthiazol- uration of the C–N chiral axis with the concomitant creation of idinethiones 38, developed by Doğan's group as heterodiene one stereogenic center with an average of 66:34 dr and partners in exo-selective inverse-electron-demand Diels–Alder ≥86 % ee for each syn and anti diastereomer. Their mechanistic cycloaddition with norbornene (Scheme 18).[30] The cycloaddi- experiments argue for lower barriers to rotation in N-arylox- tion proceeded smoothly to give the corresponding adducts azolidinones 44 than in the starting benzoylformamides 43, as 39a and 39b at room temperature with a transient kinetic corroborated by the thermally induced atropisomerization of atroposelectivity of 11:1 (R1 = Br, R2 = H), with equilibration optically pure anti-44 in favor of the corresponding ent-syn-44 after 24 h to the isolated thermodynamic ratio of 2:1 in favor photoproduct without the C-5 stereogenic center being af- of 39a, regardless of the substitution patterns. This phenome- fected (Scheme 20b).

perature, resulting in a large increase in the diastereomeric ratio (1:1 to 9:1 dr) in favor of syn-46 (“save”), due to the restricted rotation around the C–N axes (Scheme 21b). Finally, the 1:1 syn/anti ratio can be restored by heating (“erase”) the 9:1 mixture in the absence of the guest. More recently, Doğan reported the atropodiastereoselective synthesis of axially chiral thiohydantoin derivatives 49 through the reaction between amino acid ester salts and o-arylisothio- cyanates 48 in the presence of a base (Scheme 22).[34] Moderate diastereoselectivities were achieved and could be increased by recrystallization. Bulky substituents R3 were necessary to avoid racemization of the stereogenic center during the heterocycliza- tion step.

Scheme 20. Photochemical synthesis and atropisomerization of N-aryloxazol- idinones 44.

3.2. Diastereoselective Construction of the Stereogenic Scheme 22. Atropodiastereoselective synthesis of thiohydantoins 49. Chemical Bond Very recently, Wencel-Delord and Colobert reported elegant The direct stereoselective construction of the axially chiral bond intermolecular atropodiastereoselective C–N bond cross-cou- constitutes a challenging synthetic task and only few examples pling between indolines and optically pure chiral sulfoxide iod- have been proposed to date. A simple transamidation approach anes 50 (Scheme 23).[35] The use of these highly electrophilic between pyromellitic dianhydride (45) and 2-amino-3-methyl- coupling partners allowed this CuI-catalyzed C–N bond Ull- benzoic acid, giving access to the expected atropisomeric di- mann-type coupling to be performed at low temperature, en- acids as a 1:1 mixture of syn and anti conformers 46, was dis- suring the configurational stability of atropisomers 51. The use closed by Shimizu's group (Scheme 21a).[33] Both atropisomers of the sulfoxide function as a traceless auxiliary is interesting were found to be stable at room temperature, as illustrated by because many post-functionalizations are available. As an ex- calculated ∆G‡ values of 122.9 to 142.1 kJ mol–1, and have dif- ample, the atropisomer 51a was converted into axially chiral ferent hydrogen-bonding affinities toward ethyl adenine-9-acet- aldehyde 52 with complete retention of C–N bond stereogenic- ate (47) as a guest. This was exploited to devise new thermally ity. induced conformationally imprinted receptors with “write, save, and erase” recognition properties. This is shown by selective H- bonding interactions between 47 and syn-46 at 90 °C (“write”) and release of the guest molecule upon cooling to room tem-

Scheme 23. Atropodiastereoselective C–N bond cross-coupling reaction.

3.3. An Update on Enantioselective Approaches

Scheme 21. Stable syn- and anti-atropisomeric diacids 46 as imprinted recep- This more appealing but highly challenging alternative tors. emerged at the beginning of the last decade and has attracted

Eur. J. Org. Chem. 2018, 2417–2431 www.eurjoc.org 2423 © 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim Microreview strong recent interest, notably with the development of organo- enantioselectivities. Interestingly, in this last transformation, catalytic transformations. It includes complementary strategies only 0.2 mol-% of chiral phosphoric acid 59 is necessary, show- based on both stoichiometric and catalytic enantioselective ing the high efficiency of this catalyst in this case. methods, starting variously with simple achiral, prochiral, or racemic precursors, which have been comprehensively reviewed very recently.[36] Therefore, the next section offers an update of this growing field, presenting the small number of very recent and elegant approaches that allow direct enantioselective access to axially chiral five-membered atropisomers. Tong and co-workers have recently proposed two complementary examples based on the strategy developed in our group[37] for the enantioselective synthesis of furan atropisomers through oxidative central-to-axial chirality conversion (Scheme 24).[38] The optically active dihydronaphthofuran precursors 54a and 54b were obtained by enantioselective phosphine-catalyzed (3+2) annulation of δ-acetoxy allenoates 53 with 2-naphthols. Subsequent DDQ oxidation resulted in total conversion of chirality in the case of 55a, whereas a slight enantiomeric erosion was observed with 55b, probably due to its lower barrier to rotation and the relatively high temperature necessary for oxidation.

Scheme 25. Organocatalytic enantioselective arylation of indoles.

Finally, Bencivenni's group developed organocatalyzed enantioselective Friedel–Crafts alkylation between inden-1-ones 63 and 2-naphthols 64, giving rise to a not so common class of atropisomers each displaying a stereogenic C(sp3)–C(sp2) bond (Scheme 26).[40] Quinidine derivative 65 was used as the organocatalyst, and bulky R2 substituent were necessary to achieve high enough barriers to rotation. In this transformation, the steric hindrance generated during the creation of the stereogenic bond, combined with the presence of the stereogenic carbon atom, govern the distribution in favor of the ap- diastereomeric conformer, through thermodynamic control. Scheme 24. Enantioselective synthesis of furan atropisomers 55 by a central- to-axial chirality conversion.

In their outstanding quest for new enantioselective atropo- selective reactions, Tan and co-workers[39] disclosed a particularly elegant and general organocatalytic method for arylation of indoles (Scheme 25). They found that the azo function acts both as a directing and as an activating group for the nucleophilic aromatic substitution of azobenzene derivatives 56 with indoles. When R3 is a hindered alkyl group, the presence of chiral phosphoric acid 57 allows the synthesis of indole derivatives 58 with excellent yields and enantioselectivities, through the formation of intermediates 61 that quickly aromatize by Scheme 26. Organocatalytic enantioselective construction of C(sp3)–C(sp2) proton elimination. The authors serendipitously discovered that atropisomers 66. when the R3 substituent is less bulky (Me or iPr), the intermediates 61 evolve differently and cyclize by intramolecular addition to the iminium ion to generate pentacyclic intermediates 62. 4. As Ligands for Metal Complexes After "-H elimination and cleavage of the C–N bond, the An important application for atropisomers displaying five-mem- atropisomers 60 are obtained in good yields and with excellent bered rings is their utilization as ligands for metals. This may

Eur. J. Org. Chem. 2018, 2417–2431 www.eurjoc.org 2424 © 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim Microreview involve either axially chiral C–N- or C–C-bonded five-membered was obtained by resolution with (R)-methylbenzylamine and heterocyclic rings. Chauvin's group, for example, reported com- also served both as a chiral discriminating agent in enantio- prehensive studies on the synthesis, resolution, and applica- meric excess determination with different chiral amines and for tions in enantioselective catalysis of atropochiral C–N-bonded derivatizations to other atropisomers.[44] The presence of the N-naphthylimidazolylphosphine BIMINAP-67a and its corre- pyrrolidine ring resulted in greatly improved ee values in rela- sponding N-methylated cation BIMIONAP-67b as new diphos- tion to other previously developed N-alkyl ligand analogues of phane ligands with similar chelating properties for palladium, 69b,[43a–43d] ranging from 88 % to 95 %.[43e] leading to the corresponding PdII complexes 67c and 67d (Scheme 27).[41a,41b] Interestingly, (aR)-(+)-67a, obtained by fractional crystallization of the (R)-α-naphthylethylamine PdII complexes, proved to be an efficient ligand for the enantioselective Tsujii–Trost allylation of dimethyl malonate.[41b]

Scheme 29. Enantioselective addition of ZnEt2 in the presence of 1-phenyl- Scheme 27. C–N-bonded atropisomeric N-naphthylimidazolylphosphine li- pyrrole ligand 69b. gands 67a and 67b and their PdII complexes 67c and 67d. Enantioenriched arylsuccinimide 72 was obtained by Interestingly, the related atropisomeric N-arylindoline-type Shimizu and collaborators by means of a transamidation strat- aminophosphine 68a, introduced by Mino and collaborators in egy with simple succinic anhydride 70 and aminophosphine 2006 and also obtained by optical resolution from their palla- 71 coupled with a chemical resolution. This new axially chiral dium(II) complexes, and the corresponding oxidized N-aryl- phosphine ligand gave only moderate enantioselectivity in indole 68b proved to be efficient ligands for enantioselective Pd0-catalyzed allylic alkylation (Scheme 30).[45] allylic alkylation catalyzed by Pd0 with either malonates or indoles as nucleophilic partners (Scheme 28).[42]

Scheme 30. Preparation of axially chiral N-arylphosphinosuccinimide ligand 72.

Another very important family of C–N-bonded non-biaryl atropisomers incorporating five-membered rings is that of N- arylazolium salts 73, precursors of N-heterocyclic carbenes (NHCs) 74, which have found many important applications in catalysis either as ligands or as catalysts (Scheme 31).[46]

Scheme 28. N-Arylindoline and N-arylindole chiral atropisomeric ligands 68a and 68b. Scheme 31. Axially chiral N-arylazolium salts 73 and N-aryl-NHCs 74.

Complementary contributions in the field of organometallic In this field, the independent pioneering contributions by catalysis appeared soon after and involve C–N-bonded atropiso- the Grubbs and Hoveyda groups in designing new chiral meric 1-N-phenylpyrrole-derived amino alcohols of type 69b nonracemic precatalysts for olefin metathesis have inspired fur- proposed by Faigl's group for the efficient enantioselective ad- ther interesting developments.[47] Their strategies are based on dition of diethylzinc to arylaldehydes (Scheme 29).[43] The opti- diastereoselective synthesis of optically pure Ru-NHC com- cally active 1-phenylpyrrole-2-carboxylic acid precursor 69a plexes, securing atropochiral stability of ortho-N-phenyl- or

N-naphthyl substituents. However, because of relatively low rotation was observed for the unsubstituted imidazolium salt barriers to rotation the situation becomes difficult to manage (R1 =R2 =R3 = H) even at –90 °C, introduction of Me or iPr with the corresponding azolium salt precursors and even more substituents at the crucial R1 position needed temperatures so when the free carbene ligands are considered. In this con- higher than 96 °C for interconversion to be observable. With text, the first insights into obtaining axially chiral azolium salts R1 = Cy, both diastereomers were found to be stable up to and their carbene analogues were reported in 2004 by Bach's 126 °C. group (Scheme 32).[48] The most promising result involves the diastereoselective synthesis of optically pure N-phenylthiazolium salt 75, a precursor of the corresponding thiazolyl- idene-NHCs 76 evaluated as catalysts in model benzoin and Setter condensations. The synthesis started with the condensa- tion of ortho-tBu-aniline (29) with α-bromomenthone in the presence of CS2, followed by cyclodehydration and subsequent oxidation (Scheme 32a). Although 75 proved to be configura- tionally stable at room temperature, the modest 40 % and 50 % ee values obtained for benzoin and Stetter reactions, respectively, suggested substantial (75:25 dr) atropisomerization of the corresponding NHCs 76 generated in situ (Scheme 32b).

Scheme 34. Axially chiral N,N-dinaphthylimidazolium salts 80.

Interestingly, base-promoted deprotonation of 80 allowed the identification of 81, a new family of stable free monomeric imidazolinylidene NHCs incorporating two identical substituted naphthyl moieties on each nitrogen atom (Scheme 35). How- ever, when R1 = Me, the atroposelectivity was lost for 81 at room temperature, but it was totally maintained with R1 = iPr or Cy, rendering the same ratio of anti-81 and syn-81 atropisomeric NHCs. This result clearly argues for preserved high rota- Scheme 32. Axially chiral N-phenylthiazolium salt 75 and N-phenyl-NHCs 76. tion barriers even after removal of the imidazolinium proton. In all cases the activation free energies (∆G‡) of atropisomerization At the same time, Helmchen proposed 77, an axially chiral for salts 80 and NHCs 81 were determined by variable-tempera- N-naphthyl ortho-diphenylphosphinoimidazolium salt precursor ture NMR analyses, showing values from 44 to 90 kJ mol–1 and of the chiral Rh complex 78, which proved to be an efficient an average decrease of 20 kJ mol–1 after deprotonation.[50b] promotor of enantioselective catalytic hydrogenation of α,"-un- Complementarily, the authors demonstrated the efficient ligand saturated esters, with up to 99 % ee (Scheme 33).[49] Interest- ability of this new family of NHCs, which was comparable with ingly, 77, easily obtained in 87:13 dr from (S,S)-1,2-diphenyleth- that of other widely used congeners, showing good catalytic ylene-1,2-diamine, proved to be conformationally stable up to 135 °C, indicating a high barrier to rotation around the stereogenic C–N axis.

Scheme 33. Axially chiral N-naphthyl ortho-diphenylphosphinoimidazolium salt 77 and Rh complex 78.

After those reports, Dorta and collaborators showed that the preparation of imidazolium salts 80 from the corresponding ethane-1,2-diamines 79, bearing alkyl substituents (Me, iPr, Cy) on the naphthyl moiety, resulted in the diastereoselective formation of (anti)-C2-symmetric and (syn)-meso atropisomers in ratio ranging from 1.1:0.9 to 3:1 (Scheme 34).[50] Whereas fast Scheme 35. Axially chiral N,N-dinaphthylimidazolinylidene NHCs 81.

Eur. J. Org. Chem. 2018, 2417–2431 www.eurjoc.org 2426 © 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim Microreview activities in Ru-, Pd-, or Al-catalyzed transformations such as ring-closing metathesis, Suzuki–Miyaura cross-coupling, Hartwig–Buchwald amination, and alkylative ring-opening of epoxides. More recently, axially chiral NHCs of the N-naphthylbenzimidazole series have been the subject of detailed experimental and theoretical studies by Chauvin and collaborators Scheme 38. Enantiomerically pure 3-phenylbenzothiophene diphosphines 85. (Scheme 36).[51a,51b] They have clearly established that enantiopure axially chiral NHCs 82, derived from the two enantiomers of imidazolium ions 67b by dephosphorylation, are configura- Related atropisomeric diphosphine derivatives, each contain- tionally stable, leading to the isolation of the two corresponding two axially chiral C–C-bonded five-membered heterocyclic ing enantiomeric Pd complexes 83. rings, are also easily available by the same resolution protocol. This is exemplified by the preparation of the two stable enantiomers of bithiophene 86a and of those of bibenzothiophene 86b (Scheme 39). This new family of atropisomers proved to be efficient ligands for the enantioselective Ru-catalyzed hydrogenation of unsaturated esters and 1,3-dicarbonyl compounds[54a–54c] or for inter- and intramolecular Heck reactions.[55]

Scheme 36. Axially chiral N-naphthylbenzimidazolinylidene NHCs 82 and its Pd complex 83.

Concurrently, the group of Wang and Shi designed the new related Pd complex (aS,S)-84, featuring a chiral nonracemic Scheme 39. Axially chiral bithiophene and bibenzothiophene ligands 86a and oxazoline ligand instead of the –PPh2 one. It was found to be 86b, respectively. efficient for catalytic enantioselective allylic arylation, resulting in the kinetic resolution of Morita–Baylis–Hillman adducts The bibenzofuran analogue was found to be configuration- (Scheme 37).[51c] ally unstable,[54c] but the corresponding bis-diphenylphosphine binaphthofuran BINAPFu (87) could be successfully prepared and resolved with (S)-camphorsulfonyl azide through a Staudinger reaction.[56] It was then found that this new ligand outperformed BINAP in the Heck reaction between phenyl tri- flate and 2,3-dihydrofuran (Scheme 40).

Scheme 37. Enantioselective allylic arylation with Pd complex 84.

Scheme 40. Bibenzofuranyl phosphine 87 as a chiral atropisomeric ligand. The resolution approach has also been exploited to obtain chiral nonracemic atropisomers featuring interesting properties Complementarily to this new series of chiral atropisomeric as new ligands for transition-metal catalysis, intensively devel- phosphine ligands, the C3–C3-bonded NH-biindolyl analogue oped by the Sannicolò group at the end of the 1990s.[52] An 88a[54d] and the corresponding C2–C2-bonded N-alkyl-biindoles interesting example can be found in the straightforward synthe- BIMPs-88b and -88c[54e,54f] were obtained enantiomerically sis of 3-arylbenzothiophene derivatives such as 85 by fractional pure by resolution from chiral palladium complexes or tartaric crystallization of the diastereomeric adducts from (R)- or (S)- acid adducts, respectively (Scheme 41a). Similarly, BIMIP- O,O′-dibenzoyltartaric acid (Scheme 38).[53] The authors showed 89a,[54e,54g] a unique example of an axially chiral N–N-bonded the excellent behavior of this atropisomeric diphosphine as li- bibenzimidazole atropisomer, could be obtained in enantio- gand either for Ru-catalyzed enantioselective hydrogenation or merically pure form by resolution of the corresponding (R)- or for Pd-catalyzed Diels–Alder cycloaddition. (S)-dimethyl naphthylethylamine palladium complexes or by

Eur. J. Org. Chem. 2018, 2417–2431 www.eurjoc.org 2427 © 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim Microreview separation by chiral HPLC (Scheme 41b). All of these unconven- also in quinoline alkynylation,[57b] the synthesis of skipped tional diphosphines have been evaluated as ligands, with diynes,[57c] and the conjugate alkynylation of Meldrum's acid variable efficiencies, in either PdII- or PtII-catalyzed Diels–Alder acceptors.[57d] cycloadditions.[54h] A similar resolution approach was used to Building on this new strategy for increasing the barrier to prepare C-naphthylbenzimidazole P,N-bidentate ligand (aS)-(–)- rotation, the same group, as well as Guiry's group, introduced BIMNAP-89b.[54i] axially chiral phosphino-imidazoline ligands 91, also featuring central chirality (Scheme 42b).[58] The synthesis is more efficient, notably avoiding the use of stoichiometric amounts of chiral palladium complex for the deracemizing step. In this case, the resolution was achieved by fractional crystallization. This ligand was found also to be very efficient in enantioselective alkynylation reactions, and interestingly both central and axial chirali- ties affect the selectivity of the reaction. Kamikawa and Uemura elegantly exploited the planar chiral-

ity of enantiomerically pure fluoroarene-Cr(CO)3 complexes 92 toward nucleophilic aromatic substitution with substituted indoles (Scheme 43).[59] The reactions proceeded in the presence of NaH at relatively high temperature but with usually very good diastereoselectivities depending on the substitution at the 2-position of the indole. When 2-substituted indoles (R5 ≠

H) were used, syn-axially chiral N-arylindole-Cr(CO)3 complexes 93 were obtained as major diastereomers (67:33 to >98:2 dr) Scheme 41. C3–C3- and C2–C2-bonded biindolyls 88a–c, N–N-bonded bi- whereas absence of substitution at C-2 resulted in the anti benzimidazolyl 89a, and C-naphthyl-bonded benzimidazolyl 89b. atropisomers 93, also with excellent diastereoselectivities (96:4 An original design for a chiral biaryl P,N-ligand was intro- to > 98:2 dr). duced by Aponick's group in 2013 (Scheme 42a).[57a] They prepared the imidazole-based biaryl P,N-ligand 90 in six steps from commercially available 2-hydroxy-1-naphthaldehyde. Two addi- tional steps, including a highly diastereoselective complexation with a chiral palladium complex, followed by decomplexation with dppe, allowed its deracemization (isolated in 98 % ee). The barrier to rotation of 90 is increased by a favorable intramolecular π-stacking interaction that stabilizes the chiral ground-state conformation. This ligand, named Stackphos, was found to be particularly efficient not only in enantioselective copper- catalyzed aldehyde-alkyne-amine coupling (A3-coupling), but

Scheme 43. From planar chirality to axially chiral N-arylindole-Cr(CO)3 complexes syn- and anti-93.

All of the examples presented until now deal with atropisomers incorporating a five-membered heterocycle. It is quite sur- prising that only one single example, reported in 1996 by Baker's group, reports the synthesis of atropisomers with an axially chiral C–C-bonded five-membered carbocyclic ring. Thus, the synthesis of enantiomerically pure chiral 1-(3′indenyl)- naphthalenes 94 was accomplished thanks to a central-to-axial chirality conversion process[60] involving double bond migra- tion (Scheme 44a).[61a] The preparation of the ligands 93a and 93b starts with 2-nitro-1-naphthol, which is first converted into the corresponding tosylate. Then, nucleophilic aromatic substitution with 2-methylindenyllithium anion leads to the centrally chiral rotamer 92 in 40 % yield. This undergoes central-to-axial chirality conversion through double bond isomerization upon Scheme 42. Aponick's five-membered-ring-containing atropisomeric warming to room temperature to furnish axially chiral 94 in P,N-ligands 90 and 91. 40 % yield. The nitro function of 94 can be easily converted into

Eur. J. Org. Chem. 2018, 2417–2431 www.eurjoc.org 2428 © 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim Microreview the corresponding amine by hydrogenation in the presence of for various metal catalysts and organocatalysts, sometimes also platinum on carbon. Also, the amine 93a can be converted into featuring interesting biological or physical properties. A signifi- the corresponding axially chiral naphthol 93b by diazotization. cant synthetic breakthrough appeared with the desymmetriza- Resolution of the ligands is achieved by semipreparative chiral tion of privileged structures such as N-arylmaleimides, -succin- HPLC. Using a related strategy with a chiral sulfoxide auxiliary, imides, and other related heterocycles, which has largely been the same team also showed the possibility of accessing enantio- developed in its diastereoselective version and to a lesser ex- merically pure axially chiral ligand 93c, bearing a hydroxy- tent in some enantioselective transformations. This last point methyl moiety on the naphthyl ring.[61b] Treatment of 93c became a tantalizing challenge and has attracted increased in- with one equivalent of Zr(NEt2)4 enantiospecifically provides terest in the last two years. Notably, thanks to the huge the planar chiral zirconium complex 95 in quantitative yield, progress in organocatalytic activation methods, various comple- thanks to a complete axial-to-planar chirality conversion step mentary enantioselective approaches have been designed, al- (Scheme 44b).[61c] lowing access to several new families of atropisomers each featuring an axially chiral C–N- or C–C- bonded five-membered heterocyclic ring of the succinimide, naphthyimide, urazole, indole, pyrrole, thiophene, or furan series. Surprisingly, only one example, reported back in 1996, describes the synthesis of atropisomers with an axially chiral C(sp2)–C(sp2) bonded five- membered carbocyclic ring, whereas an enantioselective synthesis of carbocyclic five-membered atropisomers featuring a stereogenic C(sp3)–C(sp2) chemical bond was disclosed very recently. With this historical overview, we hope that readers will be convinced that the design of ingenious methodologies is still possible and should open the way to other strategies providing new answers to this important synthetic challenge. Moreover, this should produce hitherto unknown chiral molecular species with potential applications for a wide cross-section of chemistry including chiral ligands, organocatalysts, materials, and new biologically relevant compounds.

Acknowledgments Financial support from the Agence Nationale pour la Recherche (ANR-13-BS07-0005), the Centre National de la Recherche Scien- tifique (CNRS), and Aix-Marseille Université is gratefully ac- Scheme 44. Synthesis of atropisomers with an axially chiral C–C-bonded five- knowledged. We warmly thank our colleague Professor Chris- membered carbocyclic ring. tian Roussel for fruitful discussions and sharing with us his sharp literature knowledge on atropisomerism.

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